Lung cancer is the leading cause of cancer related death accounting for more deaths than breast, prostate and colon combined. Early diagnosis is critical to patient survival, however the vast majority of lung malignancies are detected only once symptoms arise and the cancer has spread, at which time patients have little chance of cure. Macroscopic imaging modalities including CT and bronchoscopy have made significant strides in increasing early detection; however they do not have the required specificity to diagnose malignancy. Diagnosis must be made on the microscopic level, which at present can only be accomplished with excisional biopsy. Unfortunately, low-risk bronchoscopic techniques for retrieving biopsy samples are hampered by low diagnostic yields, and trans-thoracic and surgical approaches carry higher intrinsic risk of complications. Given the very high false positive rates of these macroscopic imaging platforms it is imperative that high-risk procedures are avoided and the diagnostic accuracy of lower-risk approaches is greatly improved. In this proposal we aim to dramatically increase the diagnostic yield of low-risk bronchial biopsy using novel optical imaging tools to locally guide biopsy site selection ensuring that diagnostic quality samples are obtained for both histopathology and molecular profiling. Specifically, we will develop and translate polarization-sensitive optical frequency domain imaging (PS-OFDI) systems, and novel catheters for conducting PS-OFDI of the airways and peripheral lung. We will develop and validate diagnostic criteria for evaluating the PS-OFDI images of lung cancer pathology, and we will conduct clinical studies to demonstrate the improvement in biopsy yield over conventional approaches. This work will leverage the expertise, resources and ongoing collaborative ties between investigators at Massachusetts General Hospital and NinePoint Medical. Together the strategic alliance already formed will ensure the successful translation and delivery of a powerful and robust new optical bronchoscopy tool that will likely result in an increase in the diagnostic yield of bronchial biopsy for the assessment of lung cancer.